Background Myocardial macrophages have key roles in cardiac remodeling and dysfunction. The gamma-aminobutyric acid subtype A (GABA(A)) receptor was recently found to be distributed in macrophages, allowing regulation of inflammatory responses to various diseases. This study aimed to clarify the role of GABA(A) receptor-mediated macrophage responses in pressure overload-induced heart failure. Methods and Results C57BL/6J mice underwent transverse aortic constriction for pressure-overload hypertrophy (POH) and were intraperitoneally treated with a specific GABA(A) receptor agonist (topiramate) or antagonist (bicuculline). Echocardiography, histology, and flow cytometry were performed to evaluate the causes and effects of myocardial hypertrophy and fibrosis. Activation of the GABA(A) receptor by topiramate reduced ejection fraction and fractional shortening, enlarged the end-diastolic and end-systolic left ventricular internal diameter, aggravated myocardial hypertrophy and fibrosis, and accelerated heart failure in response to pressure overload. Mechanistically, topiramate increased the number of Ly6C(low) macrophages in the heart during POH and circulating Ly6C(high) classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6C(low) macrophages toward MHCIIhigh macrophage polarization. As a result, Ly6C(low) macrophages activated the amphiregulin-induced AKT/mTOR signaling pathway, and Ly6C(low)MHCII(high) macrophage polarization increased expression levels of osteopontin and TGF-beta, which led to myocardial hypertrophy and fibrosis. Conversely, GABA(A) receptor blockage with bicuculline reversed these effects. Conclusions Control of the GABA(A) receptor activity in monocytes/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABA(A) receptor has the potential to improve pressure overload-induced heart failure.